By Aviva Regev
Faculty Peer Reviewed
Introduction
Few people these days are unaware of the “obesity epidemic,” with its inception here in the United States and its steady, insidious spread around the globe. The numbers are truly staggering: in 2008, the World Health Organization estimated that 1.5 billion adults–over 20% of the earth’s population–were overweight, and 500 million of those were classified as obese, with a body mass index greater than 30.[1] In the United States, over a third of the population is overweight, and another third is obese.[2] Perhaps most concerning is that children are affected as well: 18% of adolescents ages 12-19, 20% of children ages 6-11, and 10% of children ages 2-5 were considered obese.[2] The numbers are trending steadily up (for a visual representation of obesity in the US from 1985-2010, see the Centers for Disease Control and Prevention website).[3]
Of course, there is more to the problem than just expanding waistlines. Most people are also familiar with some of the major health problems associated with obesity: diabetes, cardiovascular disease, and cancer.[4] Add to those heavy hitters the sleep apnea, liver and gallbladder disease, osteoarthritis, stroke, and gynecological dysfunction, and we have a disease that affects every organ, spreading across the globe.
That obesity contributes to this plethora of disease is well known, but how? What is the common pathway linking excess weight to this wide range of ailments? The answer, it seems, is inflammation.
Excess adipose tissue and inflammation
Adipose tissue, it seems, is not just inert fat. In the setting of obesity, adipose tissue produces numerous inflammatory cytokines and hormones that it does not produce in “healthy weight” individuals. Why does this occur? One theory proposes that the excess nutrients lead to a state of endoplasmic reticulum (ER) stress, which activates an inflammatory cascade.[5] In other words, the processing machinery is so overwhelmed by the amount of raw materials pouring in that it sounds an alarm signal. As the fat mass increases, adipose cells become relatively hypoxic. The presence of hypoxia activates inflammatory pathways and also contributes to the ER inflammatory response.[6] Finally, the excess nutrients themselves can stimulate other immune players such as toll-like receptors, which are usually triggered by microbial pathogens and activate cellular immune responses. It is likely that all three of these pathways play a role in the chronic inflammatory state seen in obesity, and may even act synergistically.
Once these cascades get going, an impressive variety of cytokines and immune cells appear to play a role. Obese adipose tissue has been shown to produce tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6), macrophage chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and leptin [6], all of which contribute to inflammation. The activation of the c-jun terminal kinase (JNK) stress pathway and the transcription factor NF-B stimulates further production of these molecules.[7] The immune function of obese adipose tissue is also different from that of lean adipose tissue, in that obese tissue has a higher proportion of pro-inflammatory T cells which secrete interferon-gamma (IFN-), best known for its role in activating the immune system against viral or bacterial invaders.[8] Adipocytes themselves can function as phagocytic cells, and their immune function is so robust that “it is challenging to find exceptions to [the] functional and molecular overlap between fat cells and macrophages.”[9]
Why is the inflammatory cascade in obese adipose tissue allowed to continue uninhibited? There are fewer anti-inflammatory T-regulatory cells in obese tissue, which may help explain why the immune response in adipose tissue is not controlled the way an inappropriate inflammatory response normally would be.[10] Another factor contributing to this unchecked response is a relative deficiency in adiponectin, a cytokine secreted by adipose tissue. Adiponectin has anti-inflammatory and antiatherogenic properties and is found in lower levels in obese individuals.[6] Many of the cytokines activated in individual over-expanded adipocytes also act in a paracrine fashion, activating the inflammatory response in other nearby cells, and may find their way into the bloodstream, where they can have an effect on a systemic level.
Insulin Resistance
The development of insulin resistance as a result of chronic inflammation is due to a complex interplay of the pathways discussed above. TNF- was one of the first culprits identified [11], but it is not a solitary player.[12] While the exact mechanism of insulin resistance in obesity is yet to be elucidated, recent trials have evaluated whether anti-inflammatory drugs may decrease insulin resistance in type 2 diabetics. Data on whether TNF- blockade with infliximab or etanercept increases insulin sensitivity and reduces fasting blood sugar are equivocal, with some studies reporting a beneficial effect [13,14] and others reporting none.[15]
Interestingly, reduction in glycosuria with high doses of salicylates was reported over a century ago [12], though not pursued further. A study published in 2008 evaluated high-dose salsalate, a salicylate that does not have gastric toxicity, in patients with type 2 diabetes. A dose-dependent reduction in fasting blood sugars, increase in insulin levels, and decrease in C-peptide levels were observed. The higher insulin levels coupled with lower C-peptide levels suggest reduced insulin clearance as well as decreased insulin secretion, indicating an improvement in insulin sensitivity.[7] Free fatty acid levels and C-reactive protein (CRP), were also decreased at higher doses, though tinnitus was sometimes a limiting factor in the dosing. These small studies show promise, and warrant further evaluation into anti-inflammatory therapy for insulin resistance and type 2 diabetes.
Cardiovascular Disease
As with insulin resistance, no discrete molecule or pathway is responsible for cardiovascular disease in obesity. Insulin resistance, dyslipidemia, and hypertension are all more common in obese individuals and appear to be independent risk factors for cardiovascular morbidity.[6] On top of this, the activation of IL-6 and TNF- as well as high levels of leptin and low levels of adiponectin may contribute to oxidative stress and endothelial dysfunction, the inciting step in atherogenesis.[6] A meta-analysis of over 160,000 patients demonstrated a linear association between CRP and vascular and non-vascular mortality in people without a history of vascular disease [16], and numerous studies have found elevated CRP to be an independent risk factor for cardiovascular mortality even in apparently healthy adults.[17] Statins, well known for lowering LDL and reducing mortality risk from myocardial infarction and stroke, also exhibit anti-inflammatory properties. In the JUPITER trial, rosuvastatin was found to reduce the risk of cardiovascular mortality in healthy adults with elevated CRP and without hyperlipidemia [18], demonstrating that part of the mortality benefit associated with statin use is related to anti-inflammatory properties and not solely lipid-lowering effects. Increased CRP is likely a marker of inflammatory activation and not a causal factor in excess risk [19], but may be useful in risk stratifying obese individuals and adjusting therapeutic goals.
Cancer
Excess weight is a known risk factor for cancer mortality, especially from non-Hodgkin’s lymphoma; multiple myeloma; and gastrointestinal, renal, prostate, breast, and gynecological cancers. In a prospective study of 900,000 US adults, obesity was found to be responsible for up to 14% of cancer deaths in men and 20% in women.[20] Based on these results, the authors determined that over 90,000 annual cancer deaths could be prevented “if men and women could maintain normal weight.”
How does inflammation factor in to the cancer risk? The inflammatory mediators TNF- and IL-6 are well-known culprits in cancer. TNF- is thought to play a role in tumor initiation, angiogenesis, and metastasis, and is associated with multiple myeloma, bladder, liver, gastric, colon, and breast cancers.[21] IL-6, which may contribute more to tumor progression than initiation, is known for its role in Kaposi’s sarcoma, multiple myeloma, Hodgkin’s lymphoma, and colon cancer.[21]
Some of the hormones that are overproduced in obesity have been implicated in carcinogenesis as well. Leptin, for example, has a proliferative effect on esophageal, breast, and prostate cancers.[22] Insulin excess has a proliferative effect through stimulation of insulin-like growth factor-1 (IGF-1), and contributes to increased risk for colorectal, kidney, breast, endometrial, and prostate cancers.[22] Leptin and IGF-1 have a synergistic effect on growth, migration, and invasion of breast cancer cells [23], and IGF-1 independently contributes to colon and pancreatic cancer growth.[22]
Conclusion
As the concept of obesity as an inflammatory disease continues to be explored, new treatments for its myriad health consequences may become available, including immunomodulatory or anti-inflammatory regimens. Weight loss leads to a reduction in a multitude of inflammatory markers elevated in obesity, including IL-6, CRP, TNF-, and many others.[24] This effect may be responsible for the reduction in morbidity seen following weight loss either through lifestyle changes or bariatric surgery. Even with these advances, the medical community and the public should not forget that obesity is largely preventable, if individuals, policy makers, the food industry, and society as a whole work together to fight it. With 2.8 million deaths a year as well as 44% of diabetes, 23% of ischemic heart disease, and up to 40% of certain cancers due to overweight or obesity [1] and annual health care costs estimated at $147 billion for 2008 [25], it is worth the effort. If this were a virus, so deadly, so widespread, so costly, and so preventable, would we be doing more to stop it?
Aviva Regev is a 4th year medical student at NYU Langone Medical Center
Peer reviewed by Michelle McMacken, MD, Medicine (GIM), NYU Langone Medical Center
Images courtesy of Wikimedia Commons
References:
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